Loteprednol

Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax[1] and Loterex.

Loteprednol etabonate
Clinical data
Trade namesLotemax
Other names11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration
    Eye drops
    Drug classCorticosteroid; glucocorticoid
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityNone
    Protein binding95%
    MetabolismEster hydrolysis
    MetabolitesΔ1-cortienic acid and its etabonate
    Onset of action≤2 hrs (allergic conjunctivitis)
    Elimination half-life2.8 hrs
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.167.120
    Chemical and physical data
    FormulaC24H31ClO7
    Molar mass466.951 g/mol g·mol−1
    3D model (JSmol)
    Melting point220.5 to 223.5 °C (428.9 to 434.3 °F)
    Solubility in water0.0005 mg/mL (20 °C)
     NY (what is this?)  (verify)

    It was patented in 1980 and approved for medical use in 1998.[2]

    Medical uses

    Applications for this drug include the reduction of inflammation after eye surgery,[1] seasonal allergic conjunctivitis, uveitis,[3] as well as chronic forms of keratitis (e.g. adenoviral and Thygeson's keratitis), vernal keratoconjunctivitis, pingueculitis, and episcleritis.

    Contraindications

    As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viral, fungal or mycobacterial infections of the eye.[1][3][4]

    Adverse effects

    The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (5%), eye pain (2%), and foreign body sensation (2%).[5]

    Interactions

    Because long term use (>10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely.[1]

    Pharmacology

    Mechanism of action

    Pharmacokinetics

    Neither loteprednol etabonate nor its inactive metabolites Δ1-cortienic acid and Δ1-cortienic acid etabonate are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no adrenal suppression, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.[1]

    Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies.[1]

    Retrometabolic drug design

    Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ1-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of hydrocortisone.[1][4][6]

    Chemistry

    Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate). The pure chemical compound has a melting point between 220.5 °C (428.9 °F) and 223.5 °C (434.3 °F). Its solubility in water is 1:2,000,000[4], therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.[7]

    Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation.[8] (This is not the same as the etabonate ester.)

    Loteprednol etabonate

    Chemical synthesis

    [9]

    References

    1. Haberfeld, H., ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
    2. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 488. ISBN 9783527607495.
    3. Loteprednol Professional Drug Facts.
    4. Dinnendahl, V.; Fricke, U., eds. (2008). Arzneistoff-Profile (in German). 6 (22 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
    5. "HIGHLIGHTS OF PRESCRIBING INFORMATION Lotemax" (PDF). 2012.
    6. Bodor, N.; Buchwald, P. (2002). "Design and development of a soft corticosteroid, loteprednol etabonate". In Schleimer, R.P.; O'Byrne, P.M.; Szefler, S.J.; Brattsand, R. (eds.). Inhaled Steroids in Asthma. Optimizing Effects in the Airways. Lung Biology in Health and Disease, Vol. 163. Marcel Dekker, New York. pp. 541–564.
    7. "Loteprednol (Professional Patient Advice)". Retrieved October 4, 2018.
    8. Pavesio, C.E.; Decory, H.H. (2008). "Treatment of ocular inflammatory conditions with loteprednol etabonate". Br J Ophthalmol. 92 (4): 455–459. doi:10.1136/bjo.2007.132621. PMID 18245274.
    9. Druzgala, P.; Hochhaus, G.; Bodor, N. (1991). "Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate". J. Steroid Biochem. Mol. Biol. 38 (2): 149–54. doi:10.1016/0960-0760(91)90120-T. PMID 2004037.

    Further reading

    • Steward, R.; et al. (November 1998). "Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1". J Cataract Refract Surg. 24 (11): 1480–1489. doi:10.1016/s0886-3350(98)80170-3. PMID 9818338.
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